title: Synthesis and antifolate properties of 10-alkyl-5,10-dideaza analogues of methotrexate and tetrahydrofolic acid.
abstract: Synthesis of the 10-methyl and 10-ethyl analogues of 5,10-dideazatetrahydrofolic acid (DDTHF), a potent inhibitor of glycinamide ribotide (GAR) formyltransferase, is reported. Key intermediates in the process were 10-methyl- and 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acid. Condensation of the piperidine enamines of branched 4-(p-carbomethoxyphenyl)butyraldehydes with (acetoxymethylene)malononitrile afforded 1,1-dicyano-4-piperidinobutadiene 5a,b. Subsequent reaction with alcoholic ammonium hydroxide yielded the appropriately substituted 2-amino-3-cyanopyridines 6a,b. Ring closure with guanidine gave 10-methyl- and 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acids (7a,b). Coupling with diethyl glutamate followed by ester hydrolysis afforded 10-alkyl-5,10-dideazaminopterin analogues 9a,b. Hydrolysis of the 4-amino group of 7a,b yielded the 10-alkylpteroic acids, which were coupled with diethyl glutamate, hydrogenated over PtO2, and saponified to afford 10-alkyl-5,10-dideazatetrahydrofolic acids 13a,b. Aminopterin analogues 9a,b were effective inhibitors of DHFR derived from L1210, but were less potent than methotrexate for inhibition of growth of L1210 in culture. The 10-ethyl (13b) analogue of 5,10-DDTHF was about twice as potent an inhibitor of L1210 cell growth as 5,10-DDTHF, but was only 1/7 as potent for inhibition of GAR formyltransferase. 10-Methyl analogue 13a was similar in potency to 5,10-DDTHF. All of the compounds showed moderately improved transport into L1210 cells relative to methotrexate.
authors.affiliation: Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
authors.forename: J I
authors.initials: JI
authors.lastname: DeGraw
authors.forename: P H
authors.initials: PH
authors.lastname: Christie
authors.forename: R L
authors.initials: RL
authors.lastname: Kisliuk
authors.forename: Y
authors.initials: Y
authors.lastname: Gaumont
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D019877:Hydroxymethyl and Formyl Transferases; D007939:Leukemia L1210 / Q000188:drug therapy; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D051379:Mice; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D013763:Tetrahydrofolates; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases; D008727:Methotrexate